The human airway is a complex immune organ, reflecting its central role in the host response to airborne infection. Innate T cells found within the airway have the potential to play a critical role in the recognition of these pathogens, in their control, and in the acquisition of adaptive immunity. Human mucosal associated invariant T (MAIT) cells are a unique T cell population found in all humans that are characterized by the use of a semi-invariant T cell receptor (TCR;Va7.2), dependence on the non-classical (HLA-lb) molecule MRI, and their rapid effector function. We have recently found MAIT cells to be capable of the recognition of bacterially-infected epithelial cells, and to be highly enriched in the human airway and lung parenchyma. Furthermore, in an analysis of the role of MAIT cells in those infected with Mycobacterium tuberculosis (Mtb), we found these cells to be virtually absent in those with active but not latent tuberculosis. As a result, the location of MAIT cells in the human airway, in conjunction with their ability to rapidly respond to bacterially infected epithelial cells positions these cells to play a critical role in the control of intracellular infection. The specific aims of this proposal are designed to delineate the role of these cells in the human host response to airborne infection. First, while we have found that MRI-restricted MAIT cells are capable of recognizing a broad array of pathogens, the diversity of ligand and/or pathogen recognition is not known. As a result, in the first aim the full spectrum of pathogens recognized by MAIT cells will be characterized with regard to TCR usage. Second, we have found that human primary lung epithelial cells can produce INOS both in response to IFN-gamma as well as direct T cell contact. Consequently, in the second aim we will determine the contribution of MAIT cells to the production of epithelial iNOS and consequent bacterial control. Finally, in our analysis of human airway immune cells, we have observed the presence of MAIT cells in the absence of DC. Consequently, we postulate that one function of MAIT cells is to "license" lung epithelial cells resulting in the recruitment and maturation of DC. The third aim will determine the relationship of MAIT cells with airway epithelium and dendritic cells. PUBLIC HEALH RELEVANCE (from applicant): Airborne Infections due to intracellular bacteria are a frequent and severe cause of morbidity and mortality worldwide. The airway contains a number of immune effector cells, yet their role in the recognition and control of intracellular bacteria is poorly understood. This application will focus on an innate class of T cells termed mucosal associated invariant T cells (MAIT) that are highly enriched in the human airway.